Beta, gamma-dihydropolyprenyl alcohol derivatives and pharmaceutical composition containing a polyprenyl compound

ABSTRACT

A β,γ-dihydropolyprenyl alcohol derivative having the formula: ##STR1## wherein n is an integer of 5 to 7 and R is hydrogen, a lower alkyl group or an aliphatic or aromatic acyl group, is new and useful as a prophylactic therapeutic agent for human and animal immuno-deficiency deseases and phylactic agent against human and animal infectious deseases. Another disclosed polyprenyl compound is also useful as the same agent.

This application is a continuation of U.S. Ser. No. 08/442,477, filedMay 16, 1995, now abandoned, which is a continuation of U.S. Ser. No.08/144,197, filed Oct. 27, 1993, now abandoned, which is a division ofU.S. Ser. No. 08/011,197, filed Jan. 29, 1993, now U.S. Pat. No.5,280,048 which is a division of U.S. Ser. No. 07/617,939, filed Nov.26, 1990, now abandoned, which is a division of U.S. Ser. No.07/183,488, filed Apr. 8, 1988, which is a division of U.S. Ser. No.07/086,186, filed Aug. 13, 1987, which is a continuation of U.S. Ser.No. 06/498,235, filed May 26, 1983.

This invention relates to a novel β,γ-dihydropolyprenyl alcoholderivatives having the formula (I), a process for preparing the same anda pharmaceutical composition containing a polyprenyl compound having theformula XI, XII or XIII or another polyprenyl compound, which is usefulas a prophylactic therapeutic agent for human and animalimmuno-deficiency diseases and a phylactic agent against human andanimal infectious diseases. ##STR2## wherein n is an integer of 5 to 7and R is a hydrogen atom, a lower alkyl group or an aliphatic oraromatic acyl group.

In this formula (I), the lower alkyl group in the definition of R meansC₁, to C₆ straight-chain or branched alkyl groups such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, 1-methylpropyl, tert-butyl,n-pentyl, 1-ethylpropyl, isoamyl and n-hexyl.

The novel compound having the formula (I) can be prepared by variousmethods and some typical examples will be given.

Method of Preparation 1

(a) The compound represented by the following general formula [II] isreacted with an alkyl cyano-acetate in the presence of a base to obtaina compound represented by the following general formula [III]: ##STR3##wherein n is an integer of 5 to 7; ##STR4## wherein n is an integer of 5to 7 and R is a lower alkyl group. (b) The resulting compound of formula[III] is reduced using a reducing agent such as sodium boro-hydride toobtain a compound represented by the following general formula [IV]:##STR5## wherein each of n and R has the meaning as defined above. (c)The resulting compound of formula [IV] is subjected to ester and nitrilehydrolysis in the presence of a strong alkali such as potassiumhydroxide to obtain a compound represented by the following generalformula [V]: ##STR6## wherein n has the same meaning as defined above.(d) The resulting compound of formula [V] is decarboxylated in thepresence of pyridine/copper, for example, to obtain a compoundrepresented by the following general formula [VI]: ##STR7## wherein nhas the same meaning as defined above. (e) The resulting compound offormula [VI] is reduced using a reducing agent such as lithium aluminumhydride, vitrite, sodium bis(2-methoxyethoxy) aluminum hydride or thelike, providing one of the intended compounds of the general formula[I]: ##STR8## wherein n has the same meaning as defined already. (f) Thealcoholic hydroxyl group of the compound of formula [I] is convertedinto an active group such as a tosyl or mesyl group and the compound isreacted with a corresponding alkyl alcohol in the presence of a basesuch as caustic potash to give its alkyl ether. Its ester also can bederived by reacting the compound with a corresponding aliphatic oraromatic acyl chloride or acid anhydride.

Method of Preparation 2

A compound represented by the following general formula [II] issubjected to the Wittig-Homer reaction together withtriethylphosphonoacetic acid in the presence of a base to obtain acompound represented by the following general formula [VII]: ##STR9##wherein n is an integer of 5 to 7; ##STR10## wherein n has the samemeaning as defined already.

The resulting compound of formula [VII] is hydrolyzed using a base suchas caustic potash to obtain a compound represented by the followinggeneral formula [VIII]: ##STR11## Wherein n has the same meaning asdefined already.

The compound of formula [VIII] is then reduced using metallic sodium orthe like to obtain a compound represented by the following generalformula [VI]: ##STR12##

The corresponding alcohol and its derivative can be derived by followingthe procedures of

Method of Preparation 1.

Method of Preparation 3

A compound represented by the following general formula [II] issubjected to the Witting-Hormer reaction together withdiethylphos-phonoacetonitrile in the presence of a base to obtain acompound represented by the following general formula [IX]: ##STR13##wherein n is an integer of 5 to 7; ##STR14## wherein n has the samemeaning as defined above.

The resulting compound of formula [IX] is reduced using a reducing agentsuch as metallic magnesium in a mixed solvent such as methanol/THF toobtain a compound represented by the following general formula [X]:##STR15## wherein n has the same meaning as defined above.

Next, the compound of formula [X] is hydrolyzed using caustic potash,for example, to obtain a compound represented by the following generalformula [VIII]: ##STR16##

Thereafter, the procedures of Example of Preparation 1 are followed toderive the corresponding alcohol and its derivative.

The invention further provides a pharmaceutical composition whichcomprises a pharmaceutically acceptable carrier and a pharmaceuticallyeffective amount of a polyprenyl compound selected form the groupconsisting of polyprenyl compounds having the following formulae:##STR17## wherein n is an integer of 5 to 7 and R is a lower alkyl groupor an aliphatic or aromatic acyl group; ##STR18## wherein each of a andb is hydrogen or a and b are combined together to form a bond, and n isan integer of 1 to 10; ##STR19## wherein each of a and b is hydrogen ora and b are combined together to form a bond and n is an integer of 1 to10; 3,7,11,15-tetramethylhexadeca-1-en-3-ol-;3,7,11,15-tetramethyl-1,6,10,14-hexadecatetraen-3-ol; docosanol; phytoland iso-phytol.

In other words, the above defined pharmaceutical composition contains asthe effective ingredient the novel β, γ-dihydropolyprenyl alcoholderivative as mentioned before or another polyprenyl compound.

All the above defined pharmaceutical composition is effective as aprophylactic, therapeutic agent for human and animal immuno-deficiencydiseases. Moreover, especially the composition containing the polyprenylcompound having the formula XII or XIII is useful as a phylactic agentagainst human and animal infectious deseases.

Immunology has made a remarkable progress in recent years and variousdiseases are now believed to originate from immunodeficiency. Forexample, cancer, microbism, asthma, rheumarthritis and autoimmunedisease can be cited as the diseases resulting from immunodeficiency.

In addition to simple microbism due to mere invasion of pathogenicbacteria, the increase of the complicated microbism involving variousfundamental troubles has become a serious problem. The microbism inducedby cancer, for example, is one of the most troublesome clinicalproblems. Cancer triggers the drop of general and local resistance andcomplicating and secondary diseases would occur in an easily infectivestate. Infection due to cancer mostly, assumes the form of infectionthrough a respirator, a urinary passage, a placental passage and a skinat the initial stage and results mostly in pneumonia and sepsis at thefinal stage. The mechanism of coincidence of infection due to this tumortakes generally the following process.

With the progress of leukemia, malignant lymphoma or cancer, thefunction of normal tissue and cells, especially that of lymphatic cellsand granulocyte cells is reduced so that a patient is easily infectedand infectious diseases occur coincidently. In such a case, the dose ofantibiotics does not result in radical cure but mostly in such problemsas repeated infection, microbial substitution or refractory infection.Accordingly, radical cure can not be expected by use of the conventionalantibiotics and chemotherapeutic agents but can be cured only after abiophylactic function is improved. Hence, development of drugs forimproving the biophylactic function of organism has been earnestlyawaited.

On the other hand, antibiotics have been used primarily to curebacterial infection of animals such as livestock and poultry and, as amatter of fact, various antibiotics have reduced the number or kinds ofserious infectious diseases due to pathogenic bacteria. In the livestockindustry, however, the abuse of antibiotics has caused a serious socialproblem such as residual drugs in various products, increase ofdrug-resistant bacteria and microbial substitution. In other words, thephylactic power of host is reduced remarkably and a restorative functionagainst infectious diseases is also impaired so that the microbism isdifficult to cure and the host is liable to suffer from reinfection.Furthermore, spontaneous infectious diseases (opportunistic infection)reduce the producibility of livestock and its loss is great. Hence, theimmunological competence of the host and the biophylactic function mustbe enhanced.

Under these circumstances, the inventors of the present invention havemade intensive studies in search of drugs that normalize animmunological function and enhance a biophylactic function, and havefound unexpectedly that a polyprenyl compound as defined above iseffective as a prophylactic/therapeutic agent for human and animalimmuno-deficiency diseases and especially as a phylactic agent againsthuman and animal infectious diseases:

In other words, the compound of the present invention is effective innormalizing human and animal immunological functions and enhancingresistance against the infection. Hence, the compound is useful as aprophylactic/therapeutic agent for human and animal immunodeficiencydiseases and as a phylactic agent against a variety of infectiousdiseases.

For man, the compound of the present invention is effective forrheumarthritis, autoimmune disease, cancer, asthma, various infectiousdiseases such as sepsis, pneumonia, meningitis and other viralinfectious diseases.

For animals, the compound of the present invention is effective forswine diarrhea, pneumonia (SEP, AR, haemophilus, pasteurella) and TGE,avian pneumonia (mycoplasma, haemophilus) and Marek's diseases, andbovine diarrhea, pneumonia and mastitis.

In curing human and animal infectious diseases by the compound of thepresent invention, the therapeutic effect can be improved remarkably bythe use of the present compound in combination with antibiotics. This issignificant because the aforementioned social problem of the abuse ofantibiotics can also be solved.

In the case of animals such as the livestock and poultry, the compoundof the present invention enhances the resistance of organism againstinfection and hence the compound is effective as a basal drug fornewborn. Furthermore, it is effective for mitigating the stressresulting from mass raising, transportation, and the like and is alsouseful for improving the vaccinal effect.

Accordingly, it is another purpose of the present invention to provide anovel prophylactic/therapeutic composition for human and animalimmunodeficiency.

It is further purpose of the present invention to provide a novelphylactic composition against human and animal infectious diseases.

The following compounds are typical examples of polyprenyl alcoholshaving the formulae (XI) and (XII), but it is to be noted that they aremerely illustrative but not limitative in any manner.

3,7,11,15,19,23,27,31-octamethyl-2,6,10,14,18,22,26,30-dotriacontaoctaen-1-ol

3,7,11,15,19,23,27,31,35-nonamethyl-2,6,10,14,18,22,26,30,34-hexatriacontanonaen-1-ol

3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaen-1-ol

3,7,11,15,19,23,27,31,35,39,43-undecamethyl-2,6,10,14,18,22,26,30,34,38,42-tetratetraconta-undecaen-1-ol

3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18,22, 26-octacosaheptaen-1-ol

3,7,11,15,19,23-hexamethyl-2,6,10,14,18,22-tetracosahexaen-1-ol

3,7,11,15,19-pentamethyl-2,6,10,14,18-eicosaoentaen-1-ol

3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol

3,7,11-trimethyl-2,6,10-dodecatrien-1-ol

3,7-dimethyl-2,6-octadien-1-ol

3,7,11,15,19,23,27,31,35-nonamethyl-6,10,14,18,22,26,30,34-hexatriacontaoctaen-1-ol

3,7,11,15,19,23,27,31,35,39-decamethyl-6,10,14,18,22,26,30,34,38-tetracontanonaen-1-ol

3,7,11,15,19,23,27,31,35,39,43-undecamethyl-6,10,14,18,22,26,30,34,38,42-tetratetracontadecaen-1-ol

3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-1-ol

3,7,11,15-tetramethyl-6,10,14-hexadecatrien-1-ol

3,7,11-trimethyl-6,10-dodecadien-1-ol

3,7-dimethyl-6-octen-1-ol

3,7,11,15,19,23-hexamethyl-6,10,14,18,22tetracosapentaen-1-ol

3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22, 26-octacosahexane-1-ol

3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaen-1-ol

The compound having the formulae [XI] and [XII] can be prepared byvarious methods. When a and b in the general formula [XII] are combinedtogether to form a bond, the compound can be prepared by those methodswhich are disclosed by Burrell et al. in J. Chem. Soc. (C), 1966, 2144,Popjak et al. in J. Biol. Chem., 237, 56 (1962), O. Isler et al. inHelv. Chim. Acta, 32, 2616 (1956), Japanese Patent Laid-Open No.31610/1978, and Japanese Patent Laid-Open No. 55506/1979, for example.

When a and b are both hydrogen atoms in the formula [XII], the compoundand the compound having the formula [XI] can be prepared by the methoddisclosed in Japanese Patent Laid-Open No. 76829/ 1980, for example.This method will be described more definitely.

(a) A lower alkyl cyanoacetate is reacted with a compound of the formula[II] ##STR20## (wherein n is an integer of 1 to 10) in the presence of abase to obtain a compound represented by the formula [III]: ##STR21##(wherein n has the same meaning as above and R is a lower alkyl group).(b) The resulting compound of formula [III] is reduced by a reducingagent such as sodium borohydride to obtain a compound represented by theformula [IV]: ##STR22## (wherein n and R have the same meaning asabove). (c) The resulting compound of the formula [IV] is decarboxylatedin the presence of a strong alkali such as potassium hydride to obtain acompound represented by the formula [XV]: ##STR23## (wherein n has thesame meaning as above). (d) The resulting compound of the formula [XV]is hydrolyzed in the presence of a strong alkali such as potassiumhydroxide to obtain a compound represented by the formula [XVI]:##STR24## (e) The intended compound of the formulae [XI] and [XII-]where a and b are hydrogen can be prepared by reducing the resultingcompound of the formula [XVI] using a reducing agent such as vitrite,lithium aluminum hydride, or the like: ##STR25## (wherein n is aninteger of 1 to 10).

The compound having the formula [XIII] is illustrated as follows:

6,10,14-trimethyl-5,9,13-pentadecatrien-2-one

6,10,14,18-tetramethyl-5,9,13,17-nonadecatetraen-2-one

6,10,14,18,22-pentamethyl-5,9,13,17,21-tricosapentaen-2-one

6,10,14,18,26-hexamethyl-5,9,13,17,21,25-heptacosahexaen-2-one

6,10,14,18,22,26,30-heptamethyl-5,9,13,17,21, 25,29-hentriacontaheptaen-2-one

6,10,14,18,22,26,30,34-octamethyl-5,9,13,17,21,25,29,33-pentatriacontaoctaen-2-one

6,10,14,18,22,26,30,34,38-nonamethyl-5,9,13,17,21,25,29,33,37-nonatriacontanonaen-2-one

6,10,14,18,22,26,30,34,38,42-decamethyl-5,9,13,17,21,25,29,33,37,41-tritetracontadecaen-2-one

6,10-dimethyl-5,9-undecadien-2-one

6-methyl-5-hepten-2-one

6,10,14,18,22,26,30,34,38,42-decamethyltritetracontan-2-one

6,10,14,18,22,26,30,34,38-nonamethyinonatriacontan-2-one

6,10,14,18,22,26,30,34-octamethylpentatriacontan-2-one

6,10,14,18,22,26,30-heptamethylhentriacontan-2-one

6,10,14,18,22,26-hexamethylheptacosan-2-one

6,10,14,18,22-pentamethyltricosapentan-2-one

6,10,14,18-tetramethylnonadecan-2-one

6,10,14-trimethylpentadecan-2-one

6,10-dimethylundecan-2-one

6-methylheptan-2-one

Though the compound of the formula [XIII] can be prepared by variousmethods, one of the ordinary methods is as follows: ##STR26## whereineach of a, b and n has the same meaning as defined already, and X is ahalogen atom.

In other words, prenyl halide represented by the general formula [XVII]and ethyl acetoacetate [XVIII] are reacted in the presence of acondensing agent such as metallic sodium, metallic potassium, sodiumethylate, sodium hydrate or the like in a solvent such as ethanol,t-butanol, dioxane, benzene or the like, whenever necessary, to effectcondensation. The resulting condensate is generally treated with analkali reagent such as a dilute aqueous caustic soda solution, a diluteaqueous caustic potash solution or the like without isolating thecondensate, so as to effect ester cleavage and decarboxylation and thusobtain the intended compound of formula [XIII].

The following are examples of the novel compound according to thepresent invention. However, these examples are merely illustrative butnot limitative in any manner.

EXAMPLE 1

3,7,11,15,19,23-Hexamethyl-6,10,14,18,22-tetracosapentaenol

40 g of 6,10,14,18,22,26-hexamethyl-5,9,13,17,21,25-heptacosahexaen-2-one, 15 g of ethyl cyanoacetate, 15 g of aceticacid and 500 ml of acetone were mixed, refluxed at 84 to 85° C. andsubjected to dehydro-condensation with stirring. After reacted for 7hours, the reaction product was washed with water and an organic layerwas isolated. While the residue was cooled by ice and stirred, 100 ml ofan ethanol solution containing 13 g of sodium borohydride was added.After the reduction was completed, the excessive reducing agent wasdecomposed by 10% acetic acid, washed with water and concentrated. Theconcentrate was dissolved in 200 ml of propylene glycol. After 26 g ofcaustic potash was added, the solution was stirred at 160° C. for 3hours. The reaction solution was cooled by ice and after 100 ml of 6Nhydrochloric acid was added, it was extracted with n-hexane. After theorganic layer was washed with water and dried, the product wasconcentrated.

42 g of a dicarboxylic acid obtained as the crude reaction product wasdissolved in 200 ml of pyridine. After 1 g of copper powder was added,the solution was heated under reflux for 2 hours for decarboxylation.Pyridine was vacuum-distilled, and 100 ml of water and 300 ml ofn-hexane were added. The copper powder was vacuum-filtered and 200 ml of1N HCl was added to the filtrate. The organic layer was washed withwater, then dried and thereafter concentrated.

The concentrate was refined into a colorless oily matter by silica gelcolumn chromatography, providing 30 g of3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenoic acid.

While being cooled by ice with stirring, the product was added dropwiseto 300 ml of an ethereal suspension of 4 g of lithium aluminum hydride.After the suspension was continuously stirred for 30 minutes, 4 ml ofwater with 4 ml of a 15% caustic soda solution and 12 ml of water weresequentially added. The precipitated crystal was filtered and washedtwice with 200 ml of ether. The filtrate was concentrated and theconcentrate was refined into a colorless oily matter by silica gelcolumn chromatography, providing the captioned3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaenol.

The physicochemical properties of the product were as follows:Elementary analysis: as C₃₀ H₅₂ O

    ______________________________________                                                          C      H                                                    ______________________________________                                        calculated (%):   84.04  12.23                                                  found (%): 84.06 12.23                                                      ______________________________________                                    

Infrared absorption spectrum (nujol): ν_(max) cm⁻¹ : 3,300, 2,930,1,650, 1,450, 1,380

NMR spectrum: δ(CDCl₃): 5.07 (m, 5H), 3.65 (t, J=7 Hz, 2H), 1.8-2.2 (m,18H), 1.67 (s, 3H), 1.59 (s, 15H), 1.1-1.8 (m, 6H), 0.90 (d, J=7 Hz,3H).

Mass (M/E): 428

EXAMPLE 2

3,7,11,15,19,23,27-Heptamethyl-6,10,14,18,22,26-octacosahexaenol

82 g of3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18,22,26-octacosaheptaenoicacid was dissolved in 1 l of n-amyl alcohol and 74 g of metallic sodiumwas added portionwise while the solution was vigorously stirred. Aftermetallic sodium was completely dissolved, the reaction solution waspoured into iced water and was made acidic by adding 300 ml of 6Nhydrochloric acid. It was then extracted with 1 l of n-hexane, washedwith water, dried and concentrated. 78 g of colorless, oily3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenoic acidwas obtained as the crude product. The product was then added dropwiseto 500 ml of an ethereal suspension of 10 g of lithium aluminum hydridewhile being cooled by ice and stirred. After stirring was continued for30 minutes, 10 ml of water with 10 ml of a 15% caustic soda solution,and 30 ml of water were sequentially added. The precipitated crystal wasfiltered and washed twice with 200 ml of ether. The filtrate wasconcentrated and the concentrate was defined by silica gel columnchromatography, providing the captioned3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol as acolorless oily matter.

The physicochemical properties were as follows:

Elementary analysis: as C₃₅ H₆₀ O

    ______________________________________                                                          C      H                                                    ______________________________________                                        calculated (%):   84.61  12.17                                                  found (%): 84.60 12.18                                                      ______________________________________                                    

Infrared absorption spectrum (nujol): ν_(max) cm⁻¹ : 3,300, 2,930,1,650, 1,450, 1,380.

NMR spectrum: δ(CDCl₃) 5.07 (m, 6H), 3.65 (t, J=7 Hz, 2H),1.8-2.2(m,22H),1.67 (s,3H),1.59 (s, 18H),1.1 -1.8(m,6H),0.90(d, J=7 Hz,3H).

Mass (M/E): 496

EXAMPLE 3

3,7,11,15,19,23,27,31-Octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenol

21 g of3,7,11,15,19,23,27,31-octamethyl-2,6,10,14,18,22,26,30-dotriacontaoctaenonitrilewas dissolved in250 ml of methanol and 100 ml of THF, and 24 g ofmetallic sodium was added. The reaction solution was stirred at roomtemperature for 30 minutes and was cooled with ice when foaming and heatgeneration were recognized. After the reaction solution was reacted for2 hours, 500 ml of 6N hydrochloric acid was added and the reactionproduct was extracted by 500 ml of n-hexane. The organic layer wasconcentrated and the concentrate was refined by silica gel columnchromatography, providing 16 g of3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenonitrlle.

The resulting compound was dissolved in 100 ml of propylene glycol and,after 12 a of caustic potash was added, the solution was stirred at 160°C. for 3 hours. The reaction solution was cooled with ice and, after 100ml of 6N hydrochloric acid was added, extraction was effected usingn-hexane. The organic layer was washed with water, dried and thenconcentrated, providing 16 g of3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenoicacid as the crude reaction product. The product was added dropwise to200 ml of an ethereal suspension of 2 g of lithium aluminum hydride.After stirring was continued for 30 minutes, 2 ml of water with 2 ml ofa 15% caustic soda solution, and 6 ml of water were sequentially added.The precipitated crystal was filtered and washed twice with 100 ml ofether. The filtrate was concentrated and the concentrate was refined bysilica gel column chromatography, providing 14 g of the captioned3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenolin a white waxy form.

The physicochemical properties were as follows:

Elementary analysis: as C₄₀ H₆₈ O

    ______________________________________                                                          C      H                                                    ______________________________________                                        calculated (%):   85.03  12.13                                                  found (%): 85.04 12.12                                                      ______________________________________                                    

Infrared absorption spectrum (nujol): ν_(max) cm⁻¹ : 3,300, 2,930,1,650, 1,450, 1,380.

NMR spectrum: δ(CDCl₃): 5.07 (m, 7H), 3.65 (t, J=7 Hz, 2H), 1.8-2.2 (m,26H), 1.67 (s, 3H), 1.59 (s, 18H), 1.1-1.8 (m, 6H), 0.90(d, J=7 Hz, 3H)

Mass (M/E): 564

EXAMPLE 4

3,7,11,15,19,23-Hexamethyl-6,10,14,18,22-tetracosapentaenyl methyl ether

4 g of 3,7,11,15,19,23-Hexamethyl-6,10,14,18,22-tetracosapentaenol wasdissolved in 20 ml of pyridine, and 10 g of p-toluenesulfonyl chloridewas added. The solution was stirred at room temperature for 2 hours. 20g of iced water was added and the solution was stirred for 30 minutes.Extraction was then made using 100 ml of n-hexane. The extract wassequentially washed with 1N hydrochloric acid and then with water, driedand concentrated. The concentrate was dissolved in 20 ml of dioxane. 10ml of sodium methylate (a 28% methanolic solution) was added and thesolution was stirred and refluxed for 4 hours. The reaction solution wascooled with ice and 50 ml of 6N hydrochloric acid was added. Extractionwas then made using 200 ml of n-hexane. The organic layer was washedwith water, dried and concentrated. The concentrate was refined bysilica gel column chromatography, providing 3 g of the captioned3,7,11,15,23-hexamethyl-6,10,14,18,22-tetracosapentaenyl methyl ether ina colorless oily form.

The physicochemical properties were as follows:

Elementary analysis: as C₃₁ H₅₄ O

    ______________________________________                                                          C      H                                                    ______________________________________                                        calculated (%):   84.09  12.29                                                  found (%): 84.09 12.30                                                      ______________________________________                                    

Infrared absorption spectrum (nujol): ν_(max) cm⁻¹ : 2,930, 2,830,1,650, 1,450, 1,380.

NMR spectrum: δ(CDCl₃) 5.08 (m, 5H), 3.37 (t, J=7 Hz, 2H), 3.30 (s, 3H),1.8-2.2 (m, 18H), 1.67 (s, 3H), 1.59 (s,15H), 1.1-1.8 (m, 5H), 0.90 (d,J=7 Hz, 3H).

Mass (M/E): 442

EXAMPLE 5

3,7,11,15,19,23,27-Heptamethyl-6,10,14,18,22,26-octacosahexaenyl acetate

3.5 g of3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenol wasdissolved in 20 ml of pyridine, and 10 ml of acetic anhydride was added.After 20 g of iced water was added, the solution was stirred for onehour and extraction was then made using 100 ml of n-hexane. The extractwas washed with 1N hydrochloric acid and then with water, dried andconcentrated. The concentrate was refined by silica gel columnchromatography, providing 3 g of the captioned3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaenyl acetatein a colorless oily form.

The physicochemical properties were as follows:

Elementary analysis: as C₃₇ H₆₂ O

    ______________________________________                                                          C      H                                                    ______________________________________                                        calculated (%):   82.46  11.60                                                  found (%): 82.45 11.60                                                      ______________________________________                                    

Infrared absorption spectrum (nujol): ν_(max) cm⁻¹ : 2,930, 1,735,1,650, 1,450, 1,380.

NMR spectrum: δ(CDCl₃) 5.07 (m, 6H), 4.08 (t, J=7 Hz, 2H), 2.02 (s, 3H),1.8-2.2 (m, 22H), 1.67 (s, 3H), 1.59 (s, 18H), 1.1-1.8 (m, 5H), 0.90 (d,J=7 Hz, 3H).

Mass (M/E): 538

EXAMPLE 6

3,7,11,15,19,23,27,31-Octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenylbenzoate

3.2 g of3,7,11,15,19,23,27,31-Octamethyl-6,10,14,18,22,26,30-dctriacontaheptanolwas dissolved in 20 ml of pyridine, and 5 g of benzoyl chloride wasadded. The solution was stirred at room temperature for 2 hours. 20 g oficed water was added and the solution was stirred for 30 minutes.Extraction was then made using 100 ml of n-hexane. The extract waswashed with 1N hydrochloric acid and then with water, dried andconcentrated. The concentrate was refined by silica gel columnchromatography, providing 2.7 g of the captioned3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaenylbenzoate in a white waxy form.

Elementary analysis: as C₄₇ H₇₂ O₂

    ______________________________________                                                          C      H                                                    ______________________________________                                        calculated (%):   84.37  10.85                                                  found (%): 84.38 10.83                                                      ______________________________________                                    

Infrared absorption spectrum (nujol) : ν_(max) cm⁻¹ : 3,030, 2,930,1,720, 1,650, 1,450, 1,380.

NMR spectrum: δ(CDCl₃) 7.20-8.15 (m, 5H), 5.07 (m, 7H), 4.36 (t, J=7 Hz,2H), 1.8-2.2 (m, 26H), 1.67 (s, 3H), 1.59 (s, 21H), 1.1-1.8 (m, 5H),0.90 (d, J =7 Hz, 3H).

Mass (M/E): 668

Next, the effect of the compound of the present invention will bedescribed in detail with reference to Experimental Examples.

Experimental Examples

1. Phylactic effect

(1) Method of experiment

The following specimen compounds were intra-muscularly administered toslc:ICR male mice (6 to 7 weeks old, weighing 22 to 30 g) in therespective amounts tabulated in Table 1. After 24 hours, Escherichiacoli obtained clinically was subcutaneously innoculated at a rate of2.8×10⁸ mouse. The survival ratio was determined from the number ofsurvivors on the seventh day from infection.

(2) Specimen compounds Compound A ##STR27##3,7,11-trimethyl-6,10-dodecadien-1-ol Compound B ##STR28##3,7,11,15-tetramethyl-2,6,10,14-hexadecatetraen-1-ol Compound C##STR29## 3,7,11,15-tetramethyl-6,10,14-hexadecatrien-1-ol Compound D##STR30## 3,7,11,15,19-pentamethyl-6,10,14,18-eicosatetraen-1-olCompound E ##STR31##3,7,11,15,19,23,27-heptamethyl-2,6,10,14,18,22,26-octacosaheptaen-1-olCompound F ##STR32## 3,7-di-methyl-2,6-octadien-1-ol Compound G##STR33##3,7,11,15,19,23,27,31,35,39-decamethyl-2,6,10,14,18,22,26,30,34,38-tetracontadecaen-1-ol

Compound H ##STR34##3,7,11,15,19,23,27,31,35,39,43-undecamethyl-6,10,14,18,22,26,30,34,38,42-tetratetra-contadecaen-1-ol

Compound I ##STR35##3,7,11,15,19,23-hexamethyl-6,10,14,18,22-tetracosapentaen-1-ol CompoundJ ##STR36##3,7,11,15,19,23,27-heptamethyl-6,10,14,18,22,26-octacosahexaen-1-olCompound K ##STR37##3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaen-1-olControl compound: MDP (AcMur-L-Ala-D-Glu)

(3) Results

The results are illustrated in Table 1.

                  TABLE 1                                                         ______________________________________                                                                  Survival ratio after                                    one week, number of                                                         Specimen  survivals/number of                                                 compound Dosage subjects                                                    ______________________________________                                        compound A     100 mg/kg   6/10 → 60(%)                                  compound B 100 mg/kg  6/10 → 61(%)                                     compound C 100 mg/kg  7/10 → 70(%)                                     compound D 100 mg/kg  6/10 → 60(%)                                     compound E  50 mg/kg  9/10 → 90(%)                                      100 mg/kg 10/10 → 100(%)                                              compound F 100 mg/kg  3/10 → 30(%)                                     compound G 100 mg/kg 10/10 → 100(%)                                    compound H 100 mg/kg  7/10 → 70(%)                                     compound I 100 mg/kg  9/10 → 90(%)                                     compound J  50 mg/kg  6/10 → 60(%)                                      100 mg/kg 10/10 → 100(%)                                              compound K  50 mg/kg  5/10 → 50(%)                                      100 mg/kg  9/10 → 90(%)                                               blank   1/80 → 1.25(%)                                                 (non-treated)                                                                 control 3.5 mg/kg   4/10 → 40(%)                                       compound (MDP)                                                              ______________________________________                                    

2. Phagocytosis-enhancing Effect of Macrophage

(1) Method and Results of Experiment

Each specimen compound was intramuscularly administered to slc; ICR malemice (8 weeks old, weighing 22 to 30 g) at a rate of 100 mg/kg. After 24hours, the carbon clearance test was conducted to measure thephagocytosis-enhancing effect of macrophages. The carbon clearance testwas carried out in accordance with the method described by G. Biozzi, B.Benacerraf and B. N. Halpern in Brit. J. Exp. Path., 24, 441-457.

The results are shown in Table 2.

In Table 2, the value of the changes in phagocytosis represents arelative value with respect to the half-value period of the blank whichwas set at 100.

                  TABLE 2                                                         ______________________________________                                                  Number      Half-value                                                                             Changes in                                       Specimen of period phagocytosis                                               compound animals (min:sec) (%)                                              ______________________________________                                        blank (non-                                                                             48          8:01     100                                              treated)                                                                      compound A 4 5:34 70                                                          compound D 4 5:30 69                                                          compound E 4 5:18 66                                                          compound G 3 6:43 84                                                          compound I 4 5:20 67                                                          compound J 4 5:15 65                                                          compound K 4 3:25 43                                                        ______________________________________                                    

In Table 2, when the phagocytosis is enhanced, the half-value perioddrops. However, at 20(%) or more, that is, when its numeric value issmaller than 80, the phagocytosis is strongly promoted. Accordingly,among the compounds of the present invention, compounds A, D, E, I, Jand K obviously have an extremely high phagocytosis-enhancing effect.

It is evident from the Experimental Examples described above that thecompound of the present invention normalizes the immunological functionand enhances resistance against infection.

The compound having the formula [XIII] was examined in the same way asbefore described.

Specimen Compounds

Compound L ##STR38##6,10,14,18,22,26-hexamethyl-5,9,13,17,21,25-heptacosahexaen-2-oneCompound M ##STR39##6,10,14,18,22,26,30-heptamethyl-5,9,13,17,21,25,29-hentriacontahepaten-2-one

Compound N ##STR40## 6,10-dimethyl-5,9-undecadien-2-one Compound O##STR41##6,10,14,18,22,26,30,34,38,42-decamethyl-5,9,13,17,21,25,29,33,37,41-tritetracontadecaen-2-one

Compound P ##STR42## 6,10-dimethylundecan-2-one Compound Q ##STR43##6,10,14-trimethylpentadecan-2-one Compound R ##STR44##6,10,14,18,22,26,3-0,34,38,42-decamethyltritetracontan-2-one

Control compound: MDP (AcMur-L-Ala-D-Glu)

Results of Experiment

The results are illustrated in Table 3.

                  TABLE 3                                                         ______________________________________                                                                  Survival ratio after                                    one week, number of                                                         Specimen  survivals/number of                                                 compound Dosage subjects                                                    ______________________________________                                        compound L      50 mg      4/10 → 40(%)                                   100 mg  9/10 → 90(%)                                                  compound M 100 mg  8/10 → 80(%)                                        compound N 100 mg  4/10 → 40(%)                                        compound O 100 mq  4/10 → 40(%)                                        compound p 100 mg  8/10 → 80(%)                                        compound Q 100 mg 10/10 → 100(%)                                       compound R 100 mg  3/10 → 30(%)                                        blank (non-   1/80 → 1.25(%)                                           treated)                                                                      control                                                                       compound 3.5 mg/kg   4/10 → 40(%)                                      (NDP)                                                                       ______________________________________                                    

                  TABLE 4                                                         ______________________________________                                                  Number      Half-value                                                                             Changes in                                       Specimen of period phagocytosis                                               compound animals (min:sec) (%)                                              ______________________________________                                        compound L                                                                              4           6:00     75                                               compound M 4 7:00 87                                                          blank (non- 48 8:01 100                                                       treated)                                                                    ______________________________________                                    

Accordingly, compounds L and M as the typical compounds of the presentinvention obviously have an extremely high effect of promotingphagocytosis.

The following compounds S, T, U and V were examined in the same way asbefore described.

Specimen Compound

Compound S ##STR45## 3,7,11,1 -tetramethylhexadeca-1-en-3-ol Compound T##STR46##

3,7,11,15-tetramethyl-1,6,10,14-hexadecatetraen-3-ol

Compound U ##STR47## docosanol Compound V ##STR48## phytol Controlcompound: -MDP (AcMur-L-Ala-D-Glu)

Results of Experiments

The results are illustrated in Table 5.

                  TABLE 5                                                         ______________________________________                                                                  Survival ratio after                                    one week, number of                                                         Specimen  survivals/number of                                                 compound Dosage subjects                                                    ______________________________________                                        compound S     100 mg/kg  10/10 → 100(%)                                 compound T 100 mg/kg 10/10 → 100(%)                                    compound U 100 mg/kg  3/10 → 30(%)                                     compound V 100 mg/kg 10/10 → 100(%)                                    blank (non-   1/80 → 1.25(%)                                           treated)                                                                      control com- 3.5 mg/kg  4/10 → 40(%)                                   pound (MDP)                                                                 ______________________________________                                    

                  TABLE 6                                                         ______________________________________                                                  Number      Half-value                                                                             Changes in                                       Specimen of period phagocytosis                                               compound animals (min:sec) (%)                                              ______________________________________                                        blank (non-                                                                             48          8:01     100                                              treated)                                                                      compound T 3 7:41 96                                                          compound V 4 5:48 72                                                        ______________________________________                                    

In Table 6, when the phagocytosis is enhanced, the half-value perioddrops. However, at 20(%) or more, that is, when its numeric value issmaller than 80, the phagocytosis is strongly promoted. Accordingly,among the compounds of the present invention, compound V exhibited aparticularly high phagocytosis-enhancing effect.

The compound of the present invention has extremely low toxicity andextremely high safety and can be dosed continuously for an extendedperiod of time. In this sense, too, the compound of the presentinvention is highly valuable.

When the compounds (A through K) described above were perorallyadministered to SD rats (weighing about 200 g) at a rate of 500 mg/kg,neither death of the subjects nor side reaction were observed at all.

The dosage of the compound of the present invention as aprophylactic/therapeutic agent against human immunodeficiency diseasesor as a phylactic agent against human infectious diseases variesremarkably depending upon the kind and degree of the diseases and uponthe kind of the compounds is not limitative, in particular. Generally,about 10 to 4,000 mg and preferably, 50 to 500 mg per adult per day isdosed either perorally or parenterally. When the compound is dosed asthe phylactic agent against infectious diseases, it may be of coursedosed in combination with antibiotics. Examples of dosage forms arepowder, fine particles, granules, tablets, capsules, injection, and soforth. In the preparation of the compound, the drug is prepared in acustomary manner using an ordinary support.

In preparing a peroral solid preparation, for example, an excipient and,if necessary, a binder, a disintegrator, a lubricant, a coloring agent,a flavoring agent and the like are added to the principal agent and themixture is then prepared in the form of a tablet, a coated tablet, agranule, powder, a capsule, and the like in a customary manner.

Examples of excipients are lactose, corn starch, refined sugar, glucose,sorbitol, crystalline cellulose, and the like. Examples of binders arepolyvinyl alcohol, polyvinyl ether, ethylcellulose, methylcellulose, gumarabic, tragacanth, gelatin, shellac, hydroxypropylcellulose,hydroxypropylstarch, polyvinylpyrrolidone, and the like. Examples ofdisintegrators are starch, agar, gelatin powder, crystalline cellulose,calcium carbonate, sodium hydrogencarbonate, calcium citrate, dextrin,pectin, and the like. Examples of lubricants are magnesium stearate,talc, polyethylene glycol, silica, hardened vegetable oil, and the like.Examples of coloring agents are those whose use for pharmaceuticals areofficially permitted. Examples of flavoring agents are cocoa powder,menthol, aromatic powder, peppermint oil, borneol, powdered cinnamonbark, and the like. Sugar coating, gelatin coating or the like may beappropriately applied to these tablets and granules.

In preparing an injection, a pH adjuster, a buffer, a stabilizer, apreserver, a solubilizer, and the like are added to the principal agent,whenever necessary, and the injection for subcutaneous, intramuscular orintravenous injection is prepared in a customary manner.

The drug of the present invention can also be dosed to the livestock andpoultry either perorally or parenterally. Peroral administration isgenerally effected by adding the drug to the feed. Parenteraladministration can be effected by preparing an injection in a customarymanner and then dosing the injection parenterally, intramascularly orintraveously.

The following are examples of preparations using3,7,11,15,19,23,27,31-octamethyl-2,6,10,14,18,22,26,30-dotriacontaoctaen-1-ol(hereinafter referred to as the "principal agent") which is one of thecompounds of the present invention.

    ______________________________________                                        Example of Preparation 1 (capsule)                                            ______________________________________                                        principal agent        5      g                                                 microcrystalline cellulose 80 g                                               corn starch 20 g                                                              lactose 22 g                                                                  polyvinylpyrrolidone 3 g                                                      total 130 g                                                                 ______________________________________                                    

The components were granulated in a customary manner and were packedinto 1,000 hard gelatin capsules. One capsule contained 5 mg of theprincipal drug.

    ______________________________________                                        Example of Preparation 2 (powder)                                             ______________________________________                                        principal drug         50     g                                                 microcrystalline cellulose 400 g                                              corn starch 550 g                                                             total 1,000 g                                                               ______________________________________                                    

The principal agent was first dissolved in acetone, then adsorbed bymicrocrystalline cellulose and thereafter dried. It was then mixed withcorn starch and was prepared in the powder form of 20-fold dilution.

    ______________________________________                                        Example of Preparation 3 (tablet)                                             ______________________________________                                        principal agent         5      g                                                corn starch 10 g                                                              lactose 20 g                                                                  calcium carboxymethylcellulose 10 g                                           microcrystalline cellulose 40 g                                               polyvinylpyrrolidone 5 g                                                      talc 10 g                                                                     total 100 g                                                                 ______________________________________                                    

The principal agent was first dissolved in acetone, then adsorbed bymicrocrystalline cellulose and thereafter dried. It was then mixed withcorn starch, lactose and calcium carboxymethylcellulose and an aqueoussolution of polyvinylpyrrolidone was added as a binder. The mixedsolution was then granulated in a customary manner. After talc as alubricant was added and mixed, the mixture was prepared in 100 mgtablets. One tablet contained 5 mg of the principal agent.

    ______________________________________                                        Example of Preparation 4 (injection)                                          ______________________________________                                        principal agent      10        g                                                Nikkol HCO-60 (product of 37 g                                                Nikko Chemical Co.)                                                           sesame oil 2 g                                                                sodium chloride 9 g                                                           propylene glycol 40 g                                                         phosphate buffer (0.1 M, 100 ml                                               pH 6.0)                                                                       distilled water q.s. ad 1,000 ml                                            ______________________________________                                    

The principal agent, Nikkol HCO-60, sesame oil and the half of propyleneglycol were mixed and heat-dissolved at about 80° C. Phosphate bufferand distilled water dissolving therein in advance sodium chloride andpropylene glycol were heated to about 80° C. and added to the solutiondescribed above to prepare 1,000 ml of an aqueous solution. Theresulting aqueous solution was dividedly charged into 2 ml ampoules.After heat-sealed, the ampoules were heat-sterilized.

One ampoule contained 20 mg of the principal agent.

The following are examples of preparations using3,7,11,15,19,23,27,31-octamethyl-6,10,14,18,22,26,30-dotriacontaheptaen-1-ol(hereinafter referred to as the "principal agent") which is one of thecompounds of the present invention.

Example of Preparation 5 (capsule)

    ______________________________________                                        Example of Preparation 5 (capsule)                                            ______________________________________                                        principal agent        5      g                                                 microcrystalline cellulose 80 g                                               corn starch 20 g                                                              lactose 22 g                                                                  polyvinylpyrrolidone 3 g                                                      total 130 g                                                                 ______________________________________                                    

The components were granulated in a customary manner and were packedinto 1,000 hard gelatin capsules. One capsule contained 5 mg of theprincipal drug.

Example of Preparation 6 (powder)

    ______________________________________                                        Example of Preparation 6 (powder)                                             ______________________________________                                        principal drug         50     g                                                 microcrystalline cellulose 400 g                                              corn starch 550 g                                                             total 1,000 g                                                               ______________________________________                                    

The principal agent was first dissolved in acetone, then adsorbed bymicrocrystalline cellulose and thereafter dried. It was then mixed withcorn starch and was prepared in the powder form of 20-fold dilution.

Example of Preparation 7 (tablet)

    ______________________________________                                        Example of Preparation 7 (tablet)                                             ______________________________________                                        principal agent         5      g                                                corn starch 10 g                                                              lactose 20 g                                                                  calcium carboxymethylcellulose 10 g                                           microcrystalline cellulose 40 g                                               polyvinylpyrrolidone 5 g                                                      talc 10 g                                                                     total 100 g                                                                 ______________________________________                                    

The principal agent was first dissolved in acetone, then adsorbed bymicrocrystalline cellulose and thereafter dried. It was then mixed withcorn starch, lactose and calcium carboxymethylcellulose and an aqueoussolution of polyvinylpyrrolidone was added as a binder. The mixedsolution was then granulated in a customary manner. After talc as alubricant was added and mixed, the mixture was prepared in 100 mgtablets. One tablet contained 5 mg of the principal agent.

    ______________________________________                                        Example of Preparation 8 (injection)                                          ______________________________________                                        principal agent       10       g                                                Nikkol HCO-60 (product of 37 g                                                Nikko Chemical Co.)                                                           sesame oil 2 g                                                                sodium chloride 9 g                                                           propylene glycol 40 g                                                         phosphoric acid buffer 100 ml                                                 (0.1M, pH 6.0)                                                                distilled water total 1,000 ml                                              ______________________________________                                    

The principal agent, Nikkol HCO-60, sesame oil and the half of propyleneglycol were mixed and heat-dissolved at about 80° C. Phosphate bufferand distilled water dissolving therein in advance sodium chloride andpropylene glycol were heated to about 80° C. and added to the solutiondescribed above to prepare 1,000 ml of an aqueous solution. Theresulting aqueous solution was dividedly charged into 2 ml ampoules.After heat-sealed, the ampoules were heat-sterilized.

One ampoule contained 20 mg of the principal agent.

Preparations using6,10,14,18,22,26-hexamethyl-5,9,13,17,21,25-heptacosahexaen-2-one(hereinafter referred to as the "principal agent"), follow.

    ______________________________________                                        Example of Preparation 9 (capsule)                                            ______________________________________                                        principal agent        5      g                                                 microcrystalline cellulose 80 g                                               corn starch 20 g                                                              lactose 22 g                                                                  polyvinylpyrrolidone 3 g                                                      total 130 g                                                                 ______________________________________                                    

After granulated in a customary manner, these components were chargedinto 1,000 hard gelatin capsules. Each capsule contained 5 mg of theprincipal agent.

    ______________________________________                                        Example of Preparation 10 (powder)                                            ______________________________________                                        principal agent        50     g                                                 microcrystalline cellulose 400 g                                              corn starch 550 g                                                             total 1,000 g                                                               ______________________________________                                    

The principal agent was first dissolved in acetone, then adsorbed bymicrocrystalline cellulose and thereafter dried.

After the dried matter was mixed with corn starch, the mixture wasprepared in the powder form of 20-fold dilution of the principal agentin a customary manner.

    ______________________________________                                        Example of Preparation 11 (tablet)                                            ______________________________________                                        principal agent         5      g                                                corn starch 10 g                                                              lactose 20 g                                                                  calcium carboxymethylcellulose 10 g                                           microcrystalline cellulose 40 g                                               polyvinylpyrrolidone 5 g                                                      talc 10 g                                                                     total 100 g                                                                 ______________________________________                                    

The principal agent was first dissolved in acetone, then adsorbed bymicrocrystalline cellulose and thereafter dried. Corn starch, lactoseand calcium carboxymethylcellulose were then added and mixed with thedried matter. After an aqueous solution of polyvinylpyrrolidone wasadded as a binder, the mixture was granulated in a customary manner.After talc as the lubricant was added, 100-mg tablets were prepared.Each tablet contained 5 mg of the principal agent.

    ______________________________________                                        Example of Preparation 12 (injection)                                         ______________________________________                                        principal agent      10        g                                                Nikkol HCO-60 (product of 37 g                                                Nikko Chemical Co.)                                                           sesame oil 2 g                                                                sodium chloride 9 g                                                           propylene glycol 40 g                                                         phosphoric acid buffer 100 ml                                                 (0.1M, pH 6.0)                                                                distilled water q.s. ad 1,000 ml                                            ______________________________________                                    

The principal agent, Nikkol HCO-60, sesame oil and the half of propyleneglycol were mixed and heat-dissolved at about 80° C. Phosphate bufferand distilled water dissolving therein in advance sodium chloride andpropylene glycol were heated to about 80° C. and added to the solutiondescribed above to prepare 1,000 ml of an aqueous solution. Theresulting aqueous solution was dividedly charged into 2 ml ampoules.After heat-sealed, the ampoules were heat-sterilized.

One ampoule contained 20 mg of the principal agent.

The embodiments of the invention in which an exclusive property orprivilege is claimed are defined as follows:
 1. A β,γ-dihydropolyprenylalcohol derivative selected from the group consisting of ##STR49##
 2. Aβ,γ-dihydropolyprenyl alcohol derivative as claimed in claim 1, whereinsaid alcohol derivative is
 3. A β,γ-dihydropolyprenyl alcohol derivativeas claimed in claim 1, wherein said alcohol derivative is
 4. Aβ,γ-dihydropolyprenyl alcohol derivative as claimed in claim 1, whereinsaid alcohol derivative is